Online - 2455-3891 Vol 13, Issue 4, 2020 Print - 0974-2441 Research Article

FORMULATION AND EVALUATION OF NEW MEDICATED GUM FOR THE TREATMENT OF NAUSEA AND VOMITING INDUCED BY CHEMOTHERAPY, RADIATION THERAPY, AND POST-OPERATIVE CONDITIONS IN CANCER

LALL DIPESH1*, RATHOR SHRUTI2, SONI PRANAY3 1Department of Pharmaceutics, School of Pharmacy, Chouksey Engineering College, Bilaspur, Chhattisgarh, India. 2Department of Pharmaceutics, LCIT School of Pharmacy, Bilaspur, Chhattisgarh, India. 3Department of Pharmacology, LCIT School of Pharmacy, Bilaspur, Chhattisgarh, India. Email: [email protected] Received: 11 January 2020, Revised and Accepted: 25 February 2020

ABSTRACT

Objective: The objective of the present study was formulation and evaluation of new medicated chewing gum for the treatment of nausea and vomiting induced by chemotherapy, radiation therapy, and post-operative conditions in cancer using ondansetron hydrochloride as drug candidate.

Methods: The medicated chewing gum of ondansetron hydrochloride (OHC) was prepared by direct compression mold method. Four formulations were selected for study which was showing good physicochemical properties and drug release. Formulations were characterized for physical evaluation, weight variation, stickiness, hardness/plasticity, in vitro drug release, estimation of chewing gum consistency and drug release study in saliva.

Results: All the formulations gave satisfactory results in physical evaluation, weight variation, stickiness, and hardness. The formulation medicated chewing gum II (MCG II) showed best in vitro drug release which is 97% in 30 min and it is also more accepted by the people. Drug release in saliva also indicated that more than 50% drug release occurs within 15 min.

Conclusion: Medicated chewing gum is a cost-effective product and also showed better compliance and increase in bioavailability.

Keywords: Ondansetron hydrochloride (OHC), MCGs, Chemotherapy-induced nausea and vomiting, Radiation therapy-induced nausea and vomiting, Post-operative nausea and vomiting, Cancer, Chewing gum.

© 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2020.v13i4.37094

INTRODUCTION chewed but not swallowed, providing a slow steady release of the medicine contained”. According to the European Pharmacopoeia, 4th edition, 2002 Medicated chewing is a new system for the prevention medicated chewing gum is intended to be chewed but not swallowed, and treatment of chemotherapy-induced nausea and vomiting (CINV), providing a slow steady release of the medicine contained. According radiation therapy-induced nausea and vomiting (RINV), and also in post- to the European Pharmacopoeia, 4th edition, 2002 medicated chewing operative nausea and vomiting (PONV) conditions. Drugs are usually gum is intended to be chewed for a certain period of time, required to formulated in variety of dosage forms like tablets, capsules, injections, deliver the dose, after which the remaining mass is discarded. During the and ointments etc. The oral drug delivery system is most chewing process, the drug contained in the gum product is released from acceptable route of drug administration due to ease of administration the mass into saliva and it could be absorbed through the oral mucosa or than other dosage forms. In addition to confectionary role, nowadays, swallowed reaching the for gastrointestinal absorption; thus, chewing gum is also showing best and convenient drug delivery two absorption pathways are possible to introduce the active ingredient, system due to rapid absorption of agents which can be absorbed by giving rise to a systemic effect. Medicated chewing gum offers a wide range oral cavity. Medicated chewing gums are more accepted by the parents of advantages that make it an excellent alternative [11-14]. Ondansetron for children as comparison to tablets, capsules, or . Medicated hydrochloride (HCl) is the drug of choice to prevent nausea and vomiting chewing gums are used to deliver drug locally or systemically. Drug can that may cause by cancer surgery, chemotherapy, and radiation treatment. be release locally for the oral treatment or may be absorbed rapidly by Oil-holding capacity (OHC) is a competitive serotonin type 3 receptor oral mucosa for systemic conditions, leading to fast onset of action and bioavailability. This avoids first-pass metabolism and also metabolism Table 1: MCGs with different concentrations of PVP, dextrose, in [1-7]. and PEG-400

Chewing gum drug delivery system is convenient, easy to administer S. No. Ingredients/quantity MCG I MCG II MCG III MCG IV anywhere, anytime, and its pleasant taste making it most patient 1. Ondansetron HCl 4.0 mg 4.0 mg 4.0 mg 4.0 mg acceptable [1]. Chewing gum usually consists of gum core, 2. Ascorbic acid 0.2 g 0.2 g 0.2 g 0.2 g which may or may not be coated. There are three methods by which 3. Beeswax 1.0 g 1.0 g 1.0 g 1.0 g medicated chewing gum can be prepared (1) fusion method, (2) cooling, 4. PVP 4.5 g 5.0 g 5.5 g 6.0 g grinding, and method, and (3) direct compression [8-10]. 5. Dextrose 0.7 g 0.8 g 0.9 g 1.0 g Chewing gum is defined by the European Pharmacopoeia and guidelines 6. oil 0.5 ml 0.5 ml 0.5 ml 0.5 ml for pharmaceutical dosage forms issued in 1991 by the Committee 7. PEG-400 0.8 g 1.0 g 1.2 g 1.2 g for Medicinal Products for Human Use (CPMP) as “solid single-dose 8. Calcium carbonate 0.5 g 0.5 g 0.5 g 0.5 g preparations with a base consisting mainly of gums that are intended to be PEG: Polyethylene glycol, HCl: Hydrochloride, PVP: Polyvinyl pyrrolidone Dipesh et al. Asian J Pharm Clin Res, Vol 13, Issue 4, 2020, 157-160

Table 2: Texture analysis data of MCGs of drug

S. No. Formulation code Texture analysis data Hardness (mean max force) (g) Firmness (mean max force) (g) Springiness mean ratio (%) 1. MCG I 1.121±0.10 600.1±0.44 6.421±0.27 2. MCG II 2.216±0.11 735.7±0.89 6.713±0.94 3. MCG III 3.121±0.08 889.7±0.35 6.820±0.39 4. MCG IV 3.227±0.42 920.5±0.64 6.514±0.62

Table 3: Drug content of medicated chewing gum

S. No. Formulation % purity 1. MCG I 95.24 2. MCG II 97.01 3. MCG III 94.22 4. MCG IV 94.84

Table 4: Consistency study of medicated chewing gum

Formulation Volunteers 1 2 3 4 5 6 MCG I + + + + + ++ MCG II ++ +++ +++ +++ ++ ++ MCG III ++ +++ +++ +++ + + MCG IV ++ ++ ++ ++ + ++ Fig. 1: Preparation of the MCGs +: Acceptable, ++: Good, +++: Very good

from mold, formulated chewing gums were weighed and wrapped properly. Optimization of various selected batches of MCGs by changing concentration of different excipients is depicted in Table 1.

Physical evaluation Physical properties such as size, shape, thickness, color, and a b c odor must be evaluated. It is very important to investigate the MCGs physically, which plays a key role and these should not be Fig. 2: (a) Formulated MCGs. (b) Formulated MCGs. (c) Formulated disregarded, it is necessary for acceptance by individuals and even MCGs also in marketing [1]. antagonists and effective in the treatment of nausea and vomiting caused Weight variation test by cytotoxic agents. OHC blocks the actions of chemicals in the body that Weight variation plays an important role in evaluation parameters, it can also trigger nausea and vomiting. Having been developed in the 1980s ensures that each of the medicated chewing gum contains the proper by GlaxoSmithKline and approved by the USFDA since January 1991, OHC amount of dug. The test was carried out by weighing the 20 mediated has demonstrated a long history of use and efficacy. Commonly formulated chewing gum individually using analytical balance, then calculating the as oral tablets, orally disintegrating tablets, and injections and available as average weight, and comparing the individual medicated chewing gum generic products as well, OHC continues to see contemporary innovations to the average [1]. in its formulation and uses [15-19]. Stickiness MATERIALS AND METHODS On plain surface, medicated chewing gum was placed, it is subjected to Materials collide with Teflon hammer with mass of 250 g for a period of 10 min. Ondansetron HCl was a gift sample. Excipients polyvinylpyrrolidone Hammering frequency was 30/min. After specified time, amount of (PVP), beeswax, dextrose, calcium carbonate, peppermint, ascorbic mass stick to hammer was observed and reported [1]. acid, and polyethylene glycol 400 (PEG-400) were of analytical or pharmaceutical grade were purchased. Test for hardness/plasticity There is no one reported method for the determination of hardness; Method of preparation hence, it was decided to use Pfizer type hardness tester for the MCGs were prepared by direct compression mold method. In this determination of hardness/plasticity of all MCG formulations [1]. method, each ingredient was weighed accurately and separately. OHC, PVP, beeswax, dextrose, calcium carbonate, peppermint oil, and In vitro drug release studies ascorbic acid, all ingredients were thoroughly mixed in ascending order A medicated chewing gum was immersed in pH maintained at of their weights in a mortar. After proper mixing, ingredients smoothly pH 6.8 (buccal cavity) then placed on magnetic stirrer and subjected to grounded in a mortar pestle and then previously weighed quantity stirring and after every 5 min interval 2 ml of solution taken out and of PEG-400 were added. Then, the whole mixture was again mixed replaced with fresh buffer solution. Sample was withdrawn at regular thoroughly in pestle mortar. After mixing and grinding, the mixture was intervals of 5, 10, 15, 20, 25, and 30 min. On completion of process, all subjected for compression into the desired molds and presses to form the collected samples were UV spectrophotometrically analyzed on medicated chewing gum, as shown in Figs. 1 and 2a-c. After removing maximum wavelength of 310 nm.

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Table 5: Cumulative percentage drug release of MCG II formulation in saliva

S. No. Time (min) % drug release Volunteer A Volunteer B Volunteer C Volunteer D Volunteer E Volunteer F 1. 0 0 0 0 0 0 0 2. 0.5 31.2±1.45 31.5±2.01 32.5±1.46 32.7±2.08 32.1±1.93 32.1±1.74 3. 1 34.9±1.94 35.6±1.23 36.6±1.84 35.2±1.67 35.8±1.07 34.1±1.28 4. 2 41.9±1.67 39.5±2.23 41.6±1.69 41.5±2.05 40.2±2.12 42.0±1.90 5. 5 43.4±2.31 44.2±1.40 42.7±1.98 43.3±1.87 43.4±1.06 44.1±1.07 6. 10 47.3±1.68 48.31±1.58 47.2±1.56 47.9±1.52 48.1±1.61 49.0±1.83 7. 15 52.4±1.23 52.66±1.62 53.2±1.73 52.1±1.64 53.6±1.37 52.5±1.46

RESULTS AND DISCUSSION In the present work, an attempt was made to develop medicated chewing gum containing OHC drug. Formulation MCG II was selected as optimized formulation for making medicated chewing gums, where ascorbic acid was used as antioxidant, dextrose was used as sweetening agent as well as bulking agent, beeswax/PVP as elastomer and gum, peppermint oil was used as flavoring agent. Optimized formulation was physically evaluated having weight a b 5.5 g, shape was cubic having thickness 1.4 cm with whitish- Fig. 3: (a) In vitro drug release study. (b) Ultraviolet color and peppermint odor. Weight variations study revealed that all spectrophotometric analysis of samples formulations are having weights in normal range. All formulations showed negligible stickiness and hardness also found within range, as shown in Table 2.

In vitro drug release, it was found that almost all formulations release more than 97% drug after 30 min. However, the optimized formulation MCG II has shown the best release as comparison to other formulations. Hence, it was selected for further study, Fig. 3a and b. The prepared formulations were analyzed for drug content and it was found that MCG II was having highest drug content, i.e., 97.01%, as shown in Table 3. MCGs were studied for consistency on human volunteer and MCG II was more accepted by human volunteers data which are tabulated in Table 4.

Drug release study in saliva is shown in Fig. 4, cumulative percentage drug release in each individual is also given in Table 5, it was observed Fig. 4: Cumulative percentage drug release of MCG II formulation that within 15 min, more than 50% of drug was released from the in saliva optimized formulation MCG II. This study revealed that the drug release was depended on the chewing frequency of the volunteer. Estimation of chewing gum consistency This study was carried out using chew out method. Dummy chewing CONCLUSION (without drug) was prepared according to optimized formula to check Medicated chewing gum OHC was successfully prepared. OHC is consistency. Then, they were given for certain human volunteer to a potent and highly selective 5-HT3 receptor antagonist having chew it [11]. important antiemetic activity and good tolerability. It is a cost-effective formulation and having better patient compliance and bioavailability. Drug release study in saliva OHC is completely absorbed by GIT which makes this as a choice of drug Medicated chewing gums are having quite different drug release in preparing medicated chewing gum of OHC. Due to hepatic first-pass process compared to conventional oral drug delivery system. In metabolism, only 60% OHC is bioavailable compared with IV route so Medicated chewing gums not only dosage form but also chewing this can be also avoided by preparing MCGs. activity of patient may also affects the drug delivery. Mechanical treatment is required to deliver the drug by the teeth but not involve In vitro drug release study indicated that drug release from formulation in dissolution. Release of drug from MCGs in saliva was studied by MCG II is best among others so it is the best formulation than others. All recruiting a panel of six members of volunteers and designed chew the parameters found to be satisfactory; hence, the therapeutic dose of OHC can be given in medicated chewing gum with optimized formula, out studies. One sample was given to each volunteer for chewing for i.e., MCGII. This study concluded that it is possible to make medicated a particular time interval period, i.e., 0.5, 1, 2, 5, 10, and 15 min. After chewing of OHC for prevention and treatment of vomiting induced by chewing, chewed out chewing gum samples collected from volunteer, CINV, RINV, and also in PONV conditions. stretched maximum, and cut into small pieces after that dispersed in a 100 ml volumetric flask having phosphate buffer pH 6.8, which AUTHORS’ CONTRIBUTIONS was then heated and sonicated for 10 min. These samples were then analyzed by UV spectrophotometer at absorption maxima 310 nm for Contribution of all authors is equal in this work. residual drug content in MCGs [1,2]. CONFLICTS OF INTEREST Amount of drug release during mastication = The total drug content – The authors declare that there are no conflicts of interest regarding the Residual drug after chewing publication of paper.

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SOURCE OF FUNDING Administration, Container, Closure and Administration Devices. Brussels, Belgium: Commission of the European Communities; 1991. Nil. 10. Dabhi P, Jivani NP. Development and validation of a selective analytical hplc method for the quantification of guaifenesin in guaifenesin REFERENCES medicated chewing gum intended for cough relief. Int J Eng Sci Comput 2019;9:22643-9. 1. Agrawal A, Sudhakar C. Design and development, characterization 11. Vagada R, Seth AK, Sachin C, Parikh P, Kheini P, Chainesh S, et al. and in vitro evaluation of medicated chewing gum: Granisetron Formulation and evaluation of novel gum based drug delivery system hydrochloride. J Drug Deliv Ther 2019;8:43-7. of an antiemetic drug. Int J Pharm Res Technol 2012;2:16-20. 2. Paradhkar M, Gajra B, Patel B. Formulation development and 12. Nazzal S, Bratbak G. Medicated chewing gums (MCG’s): Composition evaluation of medicated chewing gum of anti-emetic drug. Saudi Pharm production and mechanical testing. AAPS Pharm Sci Technol J 2016;24:153-64. 3. Wathore SA, Kale VK. Formulation and evaluation of medicated 2018;2:1-13. chewing gum of granisetron. Pharma Innov J 2019;898:283-6. 13. Konar N, Sagdic O, Toker OS, Palabiyik I. Chewing gum: Production, 4. Hamdan H, Zaini S. Effect of nicotine on schizophrenia and quality parameters and opportunities for delivering bioactive antipsychotic medications: A systematic review. Malays J Psychiatry compounds. Trends Sci Technol 2016;55:29-38. 2018;27:10-25. 14. Shaikh A, Agrawal A, Gupta M. Formulation and evaluation of 5. Al Hagbani T, Altomare C, Salawi A, Nazzal S. D-optimal mixture medicated chewing gum of dolasetron as an antiemetic agent. J Drug design: Formulation development, mechanical characterization, Deliv Ther 2017;7:125-8. and optimization of curcumin chewing gums using oppanol® B 12 15. Ondansetron Hydrochloride. Drug Bank. Available from: https://www. elastomer as a gum-base. Int J Pharm 2018;553:210-9. drugbank.ca/drugs/db00904. 6. Wessel SW, van der Mei HC, Maitra A, Dodds MW, Busscher HJ. 16. Gupta M, Dahiya J, Marwaha RK, Dureja H. Therapies in cancer Potential benefits of chewing gum for the delivery of oral therapeutics treatment: An overview. Int J Pharm Pharma Sci 2015;7:1-9. and its possible role in oral healthcare. Expert Opin Drug Deliv 17. Pramila P, Abraham A, Pawar S, Bafna V, Bansal MS. To study the 2016;13:1421-31. therapeutic management, drug related problems and concomitant use of 7. Aslani A, Ghannadi A, Rostami F. Design, formulation, and evaluation drugs in patients with cancer. Int J Pharm Pharma Sci 2017;9:139-44. of ginger medicated chewing gum. Adv Biomed Res 2016;5:130. 18. Simons D, Beighton D, Brailsford R. The effect of medicated chewing 8. John A, Kumar K, Dinesh KB. Medicated chewing gum: Modern drug gums on oral health in older people: A one year clinical trials. J Am delivery system. Univers J Pharm Sci Res 2019;5:29-39. Geriatr Soc 2010;50:1348-53. 9. Committee for Medicinal Products for Human Use. CPMP List 19. Mustafa W, Muniz G. The impact of chewing gums of eucalyptus of Allowed Terms for the Pharmaceutical Dosage Form, Route of extract: A systematic review. J Breath Res 2017;11:14-20.

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